Tropene derivatives



United States Patent l 2,804,460 TROPENE DERIVATIVES Chester J.Cavallito, Allan Poe Gray, and Wesley Lea Archer, Decatur, 111.,assignors to Irwin, Neisler and Company, Decatur, 111., a corporation ofIllinois No Drawing. Application July 15, 1955, Serial No. 522,393

6 Claims. (Cl. 260292) This invention relates to novel organic compoundsand is more particularly concerned with certain diquaternary ammonioderivatives of tropane, tropine, and tropine-like materials.

Specifically, the compounds of the present invention wherein n is aninteger from two to four, inclusive, R and R1 are lower-alkyl, andwherein said R and R1 may be the same, different or joined together toform an N-heterocyclic group, the sum of the carbon atoms in said Rs andR1 being from three to six, inclusive,

H H H H OH, =0, and monocarboxylic acid ester residue and X and X arestable, non-toxic anions.

The compounds of the present invention are crystalline solids havingrelatively high melting points and are water soluble. Preliminarypharmacological testing of these compounds has indicated that they haveutility as hypotensive agents. A distinct advantage accruing from theuse of the present compounds in animals has indicated that a floor-levelblood pressure fall is obtained, after certain minimum dosage has beenadministered. It can be administered at a very high relative dosagewithout causing untoward effects in both mice and monkeys when comparedto presently employed hypotensive agents. Further, after an initialdosage of the compounds of the present invention in animals, themaintenance dosage required to keep the blood pressure at a reducedlevel is substantially less than would normally be expected. Intravenousadministration in an aqueous solution has been the usual method ofadministration.

Preparation of the compounds of the present invention may be readilyaccomplished by providing an appropriate tropane, tropine ortropine-like derivative, and reacting this material with a suitablehalodimethylene, trimethylene or tetramethylene quaternary ammonium salthaving the following formula:

2,804,460 Patented Aug. 27, 1957 wherein n, Rs, R1 and X have thehereinbefore assigned values and X" is a halogen selected from the groupconsisting of chlorine, bromine and iodine. Reaction is normallyaccomplished by mixing the two reactants in a suitable solvent, such asacetonitrile, alcohols such as ethanol, methanol, isopropyl alcohol,propyl alcohol, isoamyl alcohol, et cetera; nitrobenzene, nitromethane,nitroethane, mixtures of dioxane and an alcohol and other polar solventsand solvent mixtures, et cetera. Normally, to insure an efficientreaction, a somewhat elevated temperature is employed, however, roomtemperature to 150 degrees centigrade is satisfactory and arefluxtemperature of about eighty to ninety degrees centigrade is preferred.Upon completion of the reaction, the reaction product may be recoveredby cooling the reaction mixture and separating the crystals which form.Purification of these crystals is accomplished in conventional manner,as by recrystallization from an appropriate solvent.

The starting materials employed in the process of the present inventionare well known in the art, and others are described in a copendingapplication of C. J. Cavallito and A. P. Gray, Serial 406,052, filedJanuary 25, 1954. One starting material which is readily available andapplicable for preparing compounds of the present invention is atropine,which is a tropane derivative containing a substituent hydrogen and analpha-(hydroxymethyl)- phenylacetic acid residue (tropic acid residue)attached to the same carbon atom. Other monocarboxylic acid esterresidues which are suitable include alkanoic, aromatic and aralkanoiccontaining up to 15 carbon atoms, such as, for example, acetoxy,propionoxy, butyroxy, benzoxy, S-(beta-naphthyl) -valeroxy,3-dimethylbutyroxy, alpha-naphthalene carboxy, veratroxy,diphenylacetoxy, 9-flu0renecarboxy, phenylacetoxy, etc. The term stable,non-toxic anions as used herein, is intended to include those which formstable quaternary salts with the type of materials here employed andwhich are substantially non-toxic when administered as hypotensiveagents. Representative anions which are suitable, include, for example,the chloride, bromide, iodide, sulfate, nitrate, citrate, lactate,tartrate, tannate, malate, et cetera.

The following examples are given to illustrate the procedure of thepresent invention, but are not to be construed as limiting.

Example 1 A solution of 33.6 grams (0.25 mole) of tropine and 68.0 grams(0.25 mole) of 3-bromopropyltrimethylammonium bromide in 300 millilitersof acetonitrile was refluxed for 24 hours. An oily precipitate formedwhich was collected and recrystallized from ethyl alcohol and ethylacetate. There was thus obtained 63.0 grams (63 percent of thetheoretical yield) of l-tropinium-3-(trimethylammonium)-propanedibromide, melting with gas evolution at 247 degrees centigrade.

Analysis.Calculated: C, 41.80; H, 7.52; Br, 39.74. Found: C, 42.03; H,7.71; Br, 39.47.

Example 2 A solution of 7.7 grams (0.055 mole) of tropine and 16.4 grams(0.055 mole) of 3-bromopropylmethylpiperidinium bromide in millilitersof acetonitrile was refluxed on a steam bath for three hours. At the endof this period, the crystalline product was filtered from the Warmsolution and recrystallized twice from a mixture of ethanol and ethylacetate to yield 5 .15 grams ofl-tropinium-3-(N-methylpiperidinium)-propane dibromide, as fine whiteneedles, which darken above 230 degrees centigrade and melt above 270degrees centigrade.

Analysis-Calculated: C, 46.16; H, 7.75; Br, 36.14. Found: C, 46.50; H,7.53; Br, 36.02.

Example 3 .A solution containing 10.0 grams (0.071 mole) of tropine and20.4 grams (0.071 mole) of 3-bromopropylmethylpyrrolidiniurn bromide in100 milliliters of acetonitrile was refluxed on the steam bath for fivehours. At the end of this time, the crude crystalline product wasfiltered from the warm solution and recrystallized twice from ethanoland ethyl acetate to yield 17.2 grams (57 percent of the theoreticalyield) of l-tropiniurn-S- (N-methylpyrrolidinium)-propane dibromide, aswhite crystals which darken at 235 degrees centigrade and decompose atabout 268 degrees centigrade.

Analysis.Calculated: C, 44.87; H, 7.53; Br, 37.32. Found: C, 44.93; H,7.23; Br, 36.93. In a manner similar to that of the above examples,1-tropanium-3- (trimethylammonium)-propane dibromide, melting above 270degrees centigrade is obtained.

Analysis.-Calculated: C, 43.53; H, 7.83; Br, 41.38. Found: C, 43.3 8;H,7.95; Br, 41.02.

Atropine may be reacted with 3-bromopropyltrimethylammonium bromide toyield 1-atropinium-3-(trimethylammonium)-propane dibromide melting at207 degrees Centigrade.

Analysis.Calculated: C, 50.18; H, 6.96; Br, 29.04. Found: C, 50.36; H,7.03; Br, 29.22.

Tropinone may be reacted with 3-bromopropyltrimethylammonium bromide toyield l-tropinonium-3-(trimethylammonium)-propa.ne dibromide having amelting 5 invention without departing from the spirit or scope thereofand it is to be understood that we limit ourselves only as defined inthe appended claims.

We claim:

1. A compound having the formula:

H H20 C CH:

+C Hz N C A 1\ l H: C H:

I nH2n I X!- B1 wherein n is an integer from two to four, inclusive, Rand R1 represent lower-alkyl radicals which may be joined together toform an N-heterocyclic group, the sum of the carbon atoms in saidradicals and group being from three to six, inclusive, A is selectedfrom the group consisting of H H H H OH monocarboxylic acid esterresidue and wherein X and X are stable, non-toxic anions.

2. 1-tropinium-3-(trimethylammonium)propane dibromide.

3. 1-tropinium-3-(N-methylpyrrolidinium)-propane dibromide.

4. 1-tropanium-3-(trimethylammonium)-propane dibromide.

5. 1-atropinium-3-(trirnetliylammonium)-propane dibromide.

6. 1-tropinonium-3-(trimethylamrnonium)-propane dibromide.

No references cited.

1.A COMPOUND HAVING THE FORMULA: WHEREIN N IS AN INTEGER FROM TWO TOFOUR, INCLUSIVE, R AND R1 REPRESENT LOWER-ALKYL RADICALS WHICH MAY BEJOINED TOGETHER TO FORM AN N-HETTEROCYCLIC GROUP, THE SUM OF THE CARBONATOMS IN SAID RADICALS AND GROUP BEING FROM THREE TO SIX, INCLUSIVE, <AIS SELECTED FROM THE GROUP CONSISTING OF.